Modulating mitochondrial function to promote proteostasis in the aging lung

调节线粒体功能以促进衰老肺部的蛋白质稳态

• 批准号: 10620774
• 负责人: NAVDEEP S CHANDEL
• 金额: $ 39.09万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620774
• 关键词: 1 year old; Acceleration; Age; Aging; Alveolar; Caenorhabditis elegans; Catalytic Domain; Cause of Death; Cell Death Induction; Cells; Cessation of life; Complex; Cytoprotection; DNA; Data; Disease; Electron Transport; Epithelial Cells; Epithelium; Exposure to; Functional disorder; Funding Opportunities; Goals; Heterozygote; Homeostasis; Human; Hypermethylation; Immune; Impairment; Individual; Infection; Influenza; Influenza A virus; Instruction; Knockout Mice; Longevity; Loss of Heterozygosity; Lung; Mitochondria; Mitochondrial Electron Transport Complex I; Modeling; Mus; NADH; Natural regeneration; Oxidative Phosphorylation; Pathology; Pathway interactions; Phenotype; Pneumonia; Predisposition; Production; Proteins; Pulmonary Pathology; Reactive Oxygen Species; Recovery; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Respiration; Respiratory physiology; Severities; Signal Transduction; Site; Stress; System; Testing; Tissues; Toxic effect; Virus Diseases; activating transcription factor; activating transcription factor 4; age related; aged; alveolar epithelium; biological adaptation to stress; cell age; human tissue; improved; lung injury; lung repair; normal aging; pharmacologic; prevent; proteostasis; repaired; response; small molecule; tissue repair

PROJECT SUMMARY Individuals aged 65 years or older account for 80-90% of deaths from influenza A virus each year. The overarching goal of this project is to systematically test the hypothesis that modulating mitochondrial function can alter lung repair after influenza A infection. In the first cycle, we generated data in the C. elegans model to suggest that the mild reduction in mitochondrial electron transport capacity during aging promotes proteostasis. To test this hypothesis in a mammalian system, we began to age Ndufs2 heterozygous (Ndufs2+/-) mice. Ndufs2 is a catalytic subunit of complex I of the mitochondrial electron transport chain. Ndufs2 heterozygous mice have a 50% reduction in maximal mitochondrial complex I capacity, but appear normal up to one year of age. In contrast, our preliminary data indicate that complete loss of Ndufs2 in alveolar epithelial cells causes the death of mice at a young age. Interestingly, loss of an accessory subunit of mitochondrial complex I, Ndufs4, which results in ~80% loss of mitochondrial complex I function (hypomorph), does not cause lung pathology at baseline. This has led us to hypothesize that mild reductions in mitochondrial complex I function will improve recovery after influenza A infection, while more severe reductions will induce high levels of ATF4 that will impair lung repair. Our preliminary data also indicate that regulatory T cells (Tregs) are essential for alveolar epithelial cell repair after influenza A virus infection. Tregs from aged mice have increased DNA hypermethylation and are unable to repair influenza A virus-induced lung injury. Thus, we will determine whether partial or complete loss of mitochondrial complex I function in Tregs prevents lung repair after influenza A virus infection. Collectively these hypotheses will be tested in three interrelated Specific Aims: (1) Does a decline in maximal mitochondrial complex I function (Ndufs2+/- mice) over a lifespan improve recovery from influenza A-induced pneumonia during aging? (2) Is ATF4 activation required for the increase in influenza A-induced lung injury induced by the complete loss or hypomorph of mitochondrial complex I function in alveolar epithelial cells? (3) Is the complete loss or hypomorph of mitochondrial complex I function in regulatory T cells (Tregs) sufficient to dampen their ability to promote tissue repair after lung injury?

项目概要 每年 65 岁或以上的人占甲型流感病毒死亡人数的 80-90%。这 该项目的总体目标是系统地测试调节线粒体功能的假设 可以改变甲型流感感染后的肺部修复。在第一个周期中，我们在秀丽隐杆线虫模型中生成数据 表明衰老过程中线粒体电子传递能力的轻度降低促进了蛋白质稳态。 为了在哺乳动物系统中检验这一假设，我们开始对 Ndufs2 杂合子 (Ndufs2+/-) 小鼠进行老化。恩杜夫斯2 是线粒体电子传递链复合物 I 的催化亚基。 Ndufs2 杂合小鼠有 最大线粒体复合物 I 容量减少 50%，但一岁前仍显示正常。在 相比之下，我们的初步数据表明，肺泡上皮细胞中 Ndufs2 的完全缺失会导致死亡 年轻时的老鼠。有趣的是，线粒体复合物 I 的一个辅助亚基 Ndufs4 的丢失， 导致约 80% 的线粒体复合物 I 功能（亚形质）丧失，在基线时不会引起肺部病理学。 这使我们推测线粒体复合物 I 功能的轻度降低将改善恢复 感染甲型流感后，更严重的减少会导致 ATF4 水平升高，从而损害肺部 维修。我们的初步数据还表明调节性 T 细胞 (Treg) 对于肺泡上皮细胞至关重要 甲型流感病毒感染后的修复。来自老年小鼠的 Tregs 的 DNA 高甲基化程度增加，并且 无法修复甲型流感病毒引起的肺损伤。因此，我们将确定是部分损失还是完全损失 Tregs 中线粒体复合物 I 功能的减弱可防止甲型流感病毒感染后的肺修复。集体 这些假设将在三个相互关联的具体目标中进行检验：（1）最大线粒体数量是否下降？ 复合物 I 功能（Ndufs2+/- 小鼠）在整个生命周期中可改善甲型流感诱导的肺炎的恢复 老化？ (2) ATF4激活是否是完全性甲型流感引起的肺损伤增加所必需的？ 肺泡上皮细胞中线粒体复合物 I 功能的丧失或亚型？ (3) 是完全损失还是 线粒体复合物 I 的亚型在调节性 T 细胞 (Treg) 中发挥作用，足以抑制其能力 促进肺损伤后的组织修复？